To evaluate the pharmacokinetics and pharmacodynamics of recombinant activated factor VII (rFVIIa).

Single‐dose pharmacokinetics of three dose levels (17.5, 35, and 70 µg/kg) of rFVIIa were investigated in 15 patients with hemophilia with severe factor VIII or factor IX deficiency (with or without inhibitors) while they were in the nonbleeding state and during bleeding episodes. Factor VII clotting activity (FVII:C) was determined 5 minutes before and at 10, 20, and 50 minutes and 2, 4, 6, 8, 12, and 24 hours after rFVIIa administration. Model‐independent pharmacokinetic analysis of FVII:C plasma concentration—time data included determination of plasma clearance, mean residence time, and volume of distribution. rFVIIa recovery was determined from the plasma FVII:C observed 10 minutes after administration. Pharmacodynamic assessments of prothrombin time, activated partial thrombo‐plastic time, and Factor X values obtained concurrently with FVII: C samples were performed.

Sufficient data to allow pharmacokinetic parameter calculation were available for 25 nonbleeding episodes in 11 patients (17.5 µg/kg, n = 8; 35 µg/kg, n = 9; 70 µg/kg, n = 8) and for five bleeding episodes in three patients (17.5 µg/kg, n = 2; 35 (µg/kg, n = 2; 35 µg/kg, n = 1). Recovery was calculated during 27 nonbleeding and 17 bleeding episodes. rFVIIa distribution volume is two to three times that of plasma. Median clearance was low—31.0 ml/hr · kg in nonbleeding episodes and 32.5 mg/hr · kg in bleeding episodes. In nonbleeding episodes, median mean residence time was 3.44 hours and median half‐life was 2.89 hours. In bleeding episodes, the elimination rate appears to be higher, with a median mean residence time of 2.97 hours and a median half‐life of 2.30 hours. Recovery was 45.6% during nonbleeding conditions and 43.5% during bleeding episodes (p = 0.0006); it was statistically lower with the highest dose level than with the 17.5 and 35 µ/kg doses (p = 0.007). A significant statistical relationship was observed between values of the prothrombin time and activated partial thromboplastin time, and values of FVII:C with use of maximum effect model.

The pharmacokinetics of rFVIIa are linear in the dose range evaluated. The results suggest potential value of prothrombin time determination in the monitoring of rFVIIa therapy.

Clinical Pharmacology and Therapeutics (1994) 55, 638–648; doi:10.1038/clpt.1994.80